Appetite depressant resin



United States Patent i APPETITE DEPRESSANT RESIN Richard Louis Markus,Montclair, audEdwaril R. Neary, Teaneclr, N .J., assiguors to WhiteLaboratories, Inc Kenilworth, N .J., a corporation of New Jersey NoDrawing. Application July 11, 1957 Serial No. 671,128

4 Claims (Cl. 167-55) Fatented, Feb. 2, 1960 ice and using variousMcllvaine citrate-phosphate bu'ifers (made from dibasic' sodiumphosphate and citric acid) the results were:

pH: Swelling (cc/gram) 2.2 96 3 64 4 62 .5 .30 6 u v5 The resin of thepresent invention can be made by a process described and claimed in acopendnig application Serial No. 439,875, filed June 28, 1954, entitledBatchwise :Copolymeriz'ation Technique, now U.S. Patent 2,810,716.

The following examples illustrate this method of making the resin, butis not to be construed as limiting:

cross-linking agent, swells appreciably in the gastric juices of thestomach thus producing an appetite depressing effect. T he resin doesnot swell appreciably with water, but does swell greatly in the gastricjuices of the stomach. The amount of this swelling effect dependsupon-the'pH of the body juices to which said resin isexposed. In thestomach, the gastric juice is about 0.1 normal hydrochloric acid and hasa pH of about 1-25. In that settingthe resin will swell up greatly byadsorbing over #100 times its dry Weight of the gastric juices. Theresin quickly loses its ability to hold gastric juices as the pH of thejuices is increased and at pHs above about 4, the resin does not holdany appreciable amount of body juices. Thus, as the resin, in tablet orwafer form, is swallowed, it swells to its maximum size in the stomachwhere it produces a feeling of fullness which serves to depress theappetite. Then as the resin passes through the stomach along thedigestive tract, the pH of the natural body fluids is increased and theresin shrinks. Thus, contrary to carboxymethylcellulose and otherbulking agents used as appetite depressants, the resin swells only inthe stomach where its swellability is useful, and does not remain bulkyafter leaving the stomach where this property is no longer desirable.

In order to have this utility as an appetite depressant, the2-vinylpyridine must be polymerized with asmall amount ofp,p-diisopropenyldiphenylmethane as acrosslinking agent. 7 cross-linkingagent is operable with 1.59 percent of the cross-linking agent being thepreferred resin. 1

The manufacture of the resin and its swellability and physicalcharacteristics may be improved by the use of certain food-gradenon-toxic polymer lubricants. e.g. Myverol and Myvacet lubricants, whichare acetylated glyceryl stearates or glyceryl distearate, etc., used .inamount of between 1 and 20 percent, preferably about 13 percent byweight of the resin. The lubricant is preferably added to the resinduring the manufacture thereof. The

use of a food grade polymer lubricant makes it easier'toseparate theresin from the drying pan, and causes :it-to lose its grittiness whenchewed.

To further illustrate the swelling characteristics of the preferredresins of the present inventiom-the swelling in terms of cubiccentimeters of hydrochloric acid solution adsorbed per gram of resin wasmeasured at various pI-ls, with the following results:

pH: Swelling (cc/gram) 0 30 1 130 2 200 About 1.3 to about 1.8 percentof the EXAMPLE 1 A mixture of 200 grams of 2-vinylpyridine and 3.18grams of p,p'ediisopropenyldiphenylmethane using 0.60 gram-ofazobisisobutyronitrile as an initiator was heated in an aqueous solutionof disodium phosphate for 150 minutes at 9.2 degrees centigrade. Theresin was separated by filtration and dried. There was thus obtained1.70v grams of resin .swellable in 0.1 N hydrochloric acid tothe extentof 130 cubic centimeters per gram, and in artificial g astic juice to.100 cubic centimeters per gram. EXAMPLE Z Into a :stirred hot salt brineconsisting of 47.6 kg. disodium phosphate (anhydrous and 72.4 litersofwater (ofa temperature of around -9-5' C.) were introduced a solutionof 3000 grams 2-vinylpyridine, 47.6 grams p,p'-diisopropenyldiphenylmethane, :and 9 grams azobisisobutyronitrile.The suspension was stirred and maintained at the temperature of about C.for at least2 hours. Then the resin was filtered from the hot brine,heated with dilute mineral acid first, thentreated with hot waterseveral times 'until the excess of acid has been removed. Then about 13percent of .a food grade lubricant (vMyvacet, one of the distilledacetylated monoglycerides) was, dissolved or suspended in a small amountof methanol and added to the fully swollen resin. The resin then wastreated and precipitated with an excess of 10 percent ammonia, washedwith soft water and subsequently dried. Approximately 2.5 kg. (-or ayield better than 80 percent) of the appetite depressant 2-vinylpyridineresin was obtained. The swelling of this type of resin was tested andfound to be 75-95 cc./ gm. in artifieial-gastricjjuice.

The p,p'-diisopropenyldiphenylmethane used to .make

Preparation: p,p-diis0propenyldiphenylmethane STEiP A To-a suspension of15.5 kilograms (116 moles of anhydrous aluminium chloride), in 22.7kilograms of carbon disulfide was added a solution of- 8.5 kilograms(108.4 moles) acetyl chloride, 6.05 kilograms (36 moles) of diphenylmethane-in 9 kilograms of carbon disu'lfide.

. In the course of 4 hours under stirring and ice-salt brine coolingduring the addition of the reagents, the inside temperature was-kept'inthe neighborhood of +3 degrees centigrade.

The mixture was allowed to stand overnight, and the next morning carbondisulfide was recovered by disti11ation at a jacket temperature of about58 degrees centigrade. After about hours of heating at this temperature,the distillation of the carbon disulfide was completed; the residue ofthe reaction mixture was cooled with well water and quenched by theaddition of crushed ice. After isolating the reaction mixture on aBuechner funnel under mild suction, the solids were washed with anexcess of water. Soon the oily particles of the reaction mixture havepenetrated the filter medium and reappeared forming a liquid secondphase in the aqueous filtrate which was subsequently discarded. Thecrude solids were air dried weighing 8.1 kilograms. Uponrecrystallization from acetone, totally 6.173 kilograms of purediketone, p,p'-dicetyldiphenylmethane, melting point 88-90 degreescentigrade were obtained, yield: 77.1 percent of the theory. Thediketone has been identified by oxime titration, according to D. M.Smith and J. Mitchell, Jr., Anal. Chem. 22:750 (1950).

STEP B To 18.9 liters of an etheric solution containing 63 moles of CHMgBr stirred in a jacketed reaction kettle were added a suspension of 6kilograms of p,p'-diacetyldi phenylmethane (from Step A) in 59.5 litersof benzene. The addition of the slurry was complete within 4 hours whilethe temperature of the jacket-cooled kettle was kept below +22 degreescentigrade. The temperature of the jacket was then gradually raised andkept at 85 degrees centigrade for the next hours during which period theether and most of the benzene were distilled off. Upon cooling, thereaction mixture was quenched with about 200 pounds of chopped ice andby the gradual addition of a solution of 3.6 kilograms of NH Cl in 12liters of soft water. The mixture was allowed to stand for 1 hour whenthe greatest part of the aqueous layer could be separated from thebenzene solution. The solids suspended in the aqueous layer wereisolated by filtration and washed subsequently with water. The remainingbenzene solution was then distilled in vacuo at a jacket temperature of42 degrees centigrade to a pasty consistency. To the mixture was thenadded 6 liters of water and the last traces of benzene were removed bydistillation in vacuo. Upon cooling about 60 pounds of chopped ice wereadded to the reaction mixture permitting the separation of the lowmelting solids by filtration of a Buechner. After washing the off-whitecolored powdery solids with Water and drying totally 7.357 kilos ofcrude diol, p,p'-diphenylmethane diisopropyl carbinol, were obtained.6000 grams of diketone could produce a theoretical maximum yield ofg:-;X6000=6760 grams of diol The crude diol of 7.357 kilograms containstherefore not more than x 100=91.8 percent of pure d10l One gram of thiscrude diol was recrystallized from the mixture of 4 cc. of benzene and0.4 cc. of cyclohexane, giving 0.065 gram of pure diol (white crystals)melting point 70-1 degrees centigrade.

STEP C To 300 grams of crude diol, p,p'-diphenylmethane diisopropylcarbinol (containing a maximum of 91.8 percent of pure diol) and 3 gramsof an inhibitor, 2.6-ditert-butyl-para-cresol, were added 600 cc. of apetroleum fraction (Shell solvent 140, boiling range 185-210 degrees) ina 3-neck flask equipped with a distilling head and heated in a bath ofabout 210 degrees centigrade. While stirring at this bath temperatureaudible dehydration took place and was completed in the course of onehour; the theoretical amount of water was carried over by the petroleumfraction azeotropically. Hot ethylene glycol (400 cc.) was thenintroduced cautiously into the mixture. As the remaining petroleumfraction was removed azeotropically the temperature of the bath wasraised gradually. There was added a'hot solution of 45 grams LiCl in 900cc. ethylene glycol, the fraction changed and the azeotropicaldistillation of the p,p'-diisopropenyldiphenylmethane (DIDM), started.The temperature of the bath was kept around 240 degrees centigrade andhot ethylene glycol was added continuously in order to replace thecarrier distilled; totally about 18,900 cc. of ethylene glycol wereadded. The yield was 178.8 grams of purep,p'-diisopropenyldiphenylmethane (DIDM), melting at 50-2 degreescentigrade; bromine titration revealed the presence of 92.2 percentunsaturation.

Assuming the maximum theoretical content of the starting material (Diol)as 91.8 percent, 276 grams of pure diol should furnish 241 grams ofDIDM.

The obtained amount of DIDM thus represents 74.2 percent yield of thetheory.

The appetite depressant resin of the invention was formulated in 0.5gram tablets and administered clinically to a series of obese patientsfor periods of 4 or more weeks. No special dietary regime other than theuse of the resin, was instituted. In one group, 2 tablets were takenthree times a day before meals, and 17 percent of the patients lost atleast one pound per week. In a second group, 3 tablets were taken 3times a day before meals, and 50 percent of the patients lost at leastone pound per week. In a third group, 3 tablets were taken twice a daybetween meals and 56 percent of the patients lost at least one pound perweek. From these and other tests doses of 2.0 grams of the resin takentwice daily between meals are believed to have the optimum weightreducing effect. No side effects were observed in any of the tests.

The appetite depressant resins may also be formulated in otherconvenient and conventional dosage forms for administration e.g. aswafers and capsules.

What is claimed is:

1. An appetite depressant resin comprising a swellable cross-linked2-vinyl pyridine-p,p'-diisopropenyldiphenylmethane resin, wherein theamount of p,p-diisopropenyldiphenylmethane cross-linking agent presentis between about 1.3 and 1.8 percent by weight of the 2-vinylpyridine.

2. An appetite depressant resin comprising a swellable cross-linked2-vinyl pyridine-p,p'diisopropenyldiphenylmethane resin, wherein theamount of p,p'-diisopropenyldiphenylmethane cross-linking agent presentis between about 1.3 and 1.8 percent by weight of the 2-vinylpyridine,into which has been incorporated a food grade polymerization lubricant.

3. An appetite depressant resin comprising a swellable cross-linked2-vinyl pyridine-p,p-diisopropenyldiphenylmethane resin, wherein theamount of p,p'-diisopropenyldiphenylmethane cross-linking agent presentis about 1.59 percent by weight of the 2-vinylpyridine.

4. The process of depressing the appetite which comprises the oraladministration of the composition of claim 1.

Am. J. of Pharmacy, vol. 126, No. 1, January 1954, pp. 10 and 17.

1. AN APPETITE DEPRESSANT RESIN COMPRISING A SWELLABLE CROSS-LINKED2-VINYL PYRIDINE-P,P''-DIISOPROPENYLDIPHENYLMETHANE RESIN, WHEREIN THEAMOUNT OF P,P''-DIISOPROPENYLDIPHENYLMETHANE CROSS-LINKING AGENT PRESENTIS BETWEEN ABOUT 1.3 AND 1.8 PERCENT BY WEIGHT OF THE 2-VINYLPYRIDINE.